Pharmacology of Cannabis

Endocannabinoids (eCBs) and their receptors are found throughout the human body: nervous system, internal organs, connective tissues, glands, and immune cells. The eCB system has a homeostatic role, having been characterized as “eat, sleep, relax, forget, and protect.”

It is known that eCBs have a role in the pathology of many disorders while also serving a protective function in certain medical conditions.

It has been proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent clinical eCB deficiency syndromes (CEDS). Deficiencies in eCB signaling could be also involved in the pathogenesis of depression. In human studies, eCB system deficiencies have been implicated in schizophrenia, multiple sclerosis (MS), Huntington’s disease, Parkinson’s disease, anorexia, chronic motion sickness, and failure to thrive in infants.

The eCB system represents a microcosm of psycho-neuroimmunology or “mind–body” medicine. The eCB system consists of receptors, endogenous ligands, and ligand metabolic enzymes. A variety of physiological processes occur when cannabinoid receptors are stimulated.

Cannabinoid receptor type 1 (CB1) is the most abundant G-protein–coupled receptor. It is expressed in the central nervous system, with particularly dense expression in (ranked in order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala. CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, connective and musculoskeletal tissues, and the gonads. CB2 is principally associated with cells governing immune function, although it may also be expressed in the central nervous system.The most well-known eCB ligands are N-arachidonyl-ethanolamide (anandamide or AEA) and sn-2-arachidonoyl-glycerol (2-AG).

AEA and 2-AG are released upon demand from cell membrane phospholipid precursors. This “classic” eCB system has expanded with the discovery of secondary receptors, ligands, and ligand metabolic enzymes. For example, AEA, 2-AG, N-arachidonoyl glycine (NAGly), and the phytocannabinoids Δ9-THC and CBD may also serve, to different extents, as ligands at GPR55, GPR18, GPR119, and several transient receptor potential ion channels (e.g., TRPV1, TRPV2, TRPA1, TRPM8) that have actions similar to capsaicin.

The effects of AEA and 2-AG can be enhanced by “entourage compounds” that inhibit their hydrolysis via substrate competition, and thereby prolong their action through synergy and augmentation. Entourage compounds include N-palmitylethanolamide (PEA), N-oleoylethanolamide (SEA), and cis-9-octadecenoamide (OEA or oleamide) and may represent a novel route for molecular regulation of endogenous cannabinoid activity.

Additional noncannabinoid targets are also linked to cannabis. G-protein–coupled receptors provide noncompetitive inhibition at mu and delta opioid receptors as well as norepinephrine, dopamine, and serotonin. Ligand-gated ion channels create allosteric antagonism at serotonin and nicotinic receptors, and enhance activation of glycine receptors. Inhibition of calcium, potassium, and sodium channels by noncompetitive antagonism occurs at nonspecific ion channels and activation of PPARα and PPARγ at the peroxisome proliferator-activated receptors is influenced by AEA.

THC is known to be the major psychoactive component of cannabis mediated by activation of the CB1 receptors in the central nervous system; however, this very mechanism limits its use due to untoward adverse effects. It is now accepted that other phytocannabinoids with weak or no psychoactivity have promise as therapeutic agents in humans. The cannabinoid that has sparked the most interest as a nonpsychoactive component is CBD.

Unlike THC, CBD elicits its pharmacological effects without exerting any significant intrinsic activity on CB1 and CB2 receptors. Several activities give CBD a high potential for therapeutic use, including antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective effects. CBD in combination with THC has received regulatory approvals in several European countries and is under study in registered trials with the FDA. And, some states have passed legislation to allow for the use of majority CBD preparations of cannabis for certain pathological conditions, despite lack of standardization of CBD content and optimal route of administration for effect.

Specific applications of CBD have recently emerged in pain (chronic and neuropathic), diabetes, cancer, and neurodegenerative diseases, such as Huntington’s disease. Animal studies indicate that a high dose of CBD inhibits the effects of lower doses of THC. Moreover, clinical studies suggest that oral or oromucosal CBD may prolong and/or intensify the effects of THC. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg per day) may exert a therapeutic effect for epilepsy, insomnia, and social anxiety disorder. Nonetheless, such doses of CBD have also been shown to cause sedation.

The Medicinal Cannabis Debate

As a Schedule I controlled substance with no accepted medicinal use, high abuse potential, concerns for dependence, and lack of accepted safety for use under medical supervision—along with a national stigma surrounding the potential harms and implication of cannabis use as a gateway drug to other substances—transitioning from a vilified substance to one with therapeutic merits has been controversial.

The United States Pharmacopoeia and the FDA have considered the complexities of regulating this plant-based therapy, including the numerous compounds and complex interactions between substances in this product, and how it might fit into the current regulatory framework of drugs in United States.

The emergence of interest in botanical medicinal cannabis is thought by many to be a collateral effect of the opioid abuse epidemic; public perception surrounding the use of medicinal cannabis suggests that this plant-based therapy is viewed as not much different than a botanical drug product or supplement used for health or relief of symptoms if disease persists.

Like some herbal preparations or supplements, however, medicinal cannabis may similarly pose health risks associated with its use, including psychoactive, intoxicating, and impairing effects, which have not been completely elucidated through clinical trials.

Proponents argue that there is evidence to support botanical medicinal cannabis in the treatment of a variety of conditions, particularly when symptoms are refractory to other therapies, including chemotherapy; that beneficial cannabinoids exist, as evidenced by single-entity agents derived from cannabis containing the compounds THC and cannabidiol (CBD); that cannabis is relatively safe, with few deaths reported from use; that therapy is self-titratable by the patient; and that therapy is relatively inexpensive compared with pharmaceutical agents.

Opponents of medicinal cannabis use argue, in part, that well-designed randomized trials to confirm benefits and harms are lacking; that it has not been subject to the rigors of the FDA approval process; that standardization in potency or quantity of pharmacologically active constituents is absent; that adverse health effects relate not only to smoking cannabis but to unmasking mental health disorders, impairing coordination, and affecting judgment; that standardization does not exist for product packaging and controls to prevent inadvertent use by minors or pets; that there is a potential for dependence, addiction, and abuse; and that costs pose a potential burden.

Regardless of personal views and perceptions, to deny or disregard the implications of use of this substance on patient health and the infrastructure of the health care system is irresponsible; clinicians must be aware of these implications and informed about how this therapy may influence practice in a variety of health care settings, including acute care.